ABSTRACT This R21 application aims to respond to ?Novel Mechanism Research on Neuropsychiatric Symptoms (NPS) in Alzheimer?s dementia (AD)? (RFA-MH-19-511) and its ?area of interest:? ?Assessments of neural circuits involved in apathy or other NPS in AD/ADRD, as compared to other neuropsychiatric diseases.? Apathy is the most common neuropsychiatric symptom in AD, with estimates as high as 57% in mild to moderate AD. Apathy in AD has been related to caregiver distress, decreased quality of life, and increased morbidity. Imaging studies of apathy in AD point to frontostriatal circuit involvement, including the anterior cingulate cortex, prefrontal cortex, and parts of the basal ganglia. The frontostriatal circuit may be involved in effort- based decision-making and executive functions, and disruption of this circuit has been hypothesized to play a pivotal role in apathy across neurodegenerative disorders. Of note, frontostriatal dysfunction has also been implicated in late-life major depression (LLMD). In order to distinguish apathy in AD from apathy in other conditions, and thus identify more specific targets for interventions, a brain network-based approach may help. Such an approach could be better informed by newer methods of conceptualizing the apathy syndrome. Traditional views of apathy as a construct have identified it as a syndrome related to low motivation. For example, apathy has been defined as loss of or diminished motivation in at least two of three domains ? goal- directed behavior, cognitive activity or emotion ? sufficient to cause significant impairment in everyday life. Yet despite identification of components of apathy, its underlying neural basis is not known. Specifically, brain networks that contribute to clinical apathy are unclear, maybe due to reliance on older views of the phenotype. More recent conceptualizations, aligned with NIMH?s RDoC initiative, tie apathy syndromes to Positive Valence Systems. These systems include: 1) Reward evaluation, including reward anticipation and reward sensitivity (the extent to which the individual is motivated by potential or actual reward, by avoiding loss or pain); 2) Effort valuation/willingness to work, processes that compute how much and what types of effort will be required; and 3) Judgment/Decision Making to act on obtaining rewards. We propose to link a Positive Valence Systems approach with clinical measures of apathy and with functional imaging to better understand apathy in the context of AD and how AD-associated apathy differs from apathy often seen in another disorder, LLMD. In sum, apathy is common in AD, but its neurocognitive and imaging underpinnings are understudied. Also, while apathy is a common feature in LLMD, research is needed to understand differences in reward-based neurobiology. Thus, we will study the following Specific Aims: Aim 1. To examine neurocognitive and neurobiological differences in patients with AD with and without apathy. Aim 2. To examine similarities and differences in clinical and neuropsychological characteristics and neuro- biological features of apathy across two neuropsychiatric conditions: AD and LLMD.